Substituted pyridinium salts



Patented Mar. 24, 1953 SUBSTITUTED PYRIDINIUM SALTS Lee C. Cheney, Fayetteville, N. Y., assignor to Bristol Laboratories Inc., Syracuse, poraticn of New York N. Y.,, a cor-.

No Drawing. Application'May 10, 1950,

Serial N0. l6 1,269. i

This invention "relatesto new substituted pyridinium salts which are useful in medicine for the treatment of certain disorders of the central nervous system such as schizophrenia. In addition, compounds of this class are valuable antibacterial and antifungal agents,

- These compounds may be represented by the general formula: r I

3X-N-CH -."11 h. wherein R representsa hydroxyalkyl group containing two to twenty carbon atoms, an alkyl group containing two'to twenty carbon atoms, a

gcarboalkoxy group or a halogen atom, X representsa non-toxic ion such as chloride, bromide, and iodide Ri and R2 represent hydrogen, an aryl group such as phenyl and naphthyl or a substituted aryl group including alkylphenyl, halogenated phenyl, alkoxyphenyl and nitrophenyl, or R1 and R2 together represent a fused ring system such as the 9-fluorenyl radical.

' The compounds of the invention are all characterized by a nuclear substituent in the pyridine ring. Bacteriological studies have revealed that the quaternary salts of the picolines ar much less active as antibacterialagents than are the corresponding alkyl pyridinium salts containing at least two carbon atoms in the substituent group.

. For example, compound A, (l-benzohydryl-2- picolinium bromide)- and compound B (l-benzohydryli-n-amylpyridinium bromide) have been :found to completely inhibitthe growth of the following representative microorganisms at the dilutions tabulated. These values, which indicate the minimum effective concentration for each compound, were obtained by the serial dilultionme thod in broth, incubated at 37 C. for 18 ;hours and read by visual observation asnegative or positive.

Maximum Dilution W h i c h o m pletely Inhibits Microorganism Growth Klebsiella ammonia- 1:800 123200 Mucosus'cr z psulatus 3 1:800 113200 Esch. c011 1:800 111600 S. ulcrum... 1:800 1:64.00 S. paratyphi A 1:1600 1:6400 'Shijellc paradysent, Flex 1:12800 1:102, 400 B; submits 1:800 1:51, 200 B. cere us. 11400 1:12, 800 B. mesentrz'eua; 1:1600 1:51, 200 Staph. aureus-eAssay. 1:6400 1:25, 600

6 Claims. (01. 260- 290) atoms.

In general, the antibacterial activity increases as the size of the nuclear substituent is increased untilthe group consists of atleast nine carbon On the other hand, substituents, comprising approximately five carbon atoms appear to exert an optimum therapeutic effect in the treatment of disorders ofthe central nervous :-system; The new compounds are prepared by causing a substituted pyridine to react with an organic halide to form a pyridinium salt. Becaus of the slow rate at which most organic chloridesreact with the pyridine compounds, we prefer to employ bromides or iodides in an inert solvent such ;as acetone to obtain the most favorable-yields,

but a solvent is not necessary. We prefer to use an excess of the halide and heat under reflux on the steam bath until the reaction has gone to completion. When the halide employed is particularly reactive, e. g. benzohydryl bromide, superior yields are obtained under anhydrous conditions. The compounds of the invention are white crystalline compounds, bitter to the taste. They are slightly soluble in water and quite soluble in ethyl alcohol.

10.5 g. (0.07 mole) of 4-n-amy1 pyridine was added toa solution of 21.6 g. (0.077 mole) of 'p-chlorobenzohydryl bromide in ml of reagent acetone. The light pink solution was refluxed for 15 hours, the solvent was removed under diminished pressure and the residual brown gum was caused to crystallize by prolonged Analysis for C23H25NBrC1:

Calculated: C, 64.1; H, 5.85 Found: C, 64.43; H, 5.79 1

EXAMPLE 2 i 1-(9-fluo1'enyl) -4-n-amylpyridinium bromide 1 To a solution of 16.2 g. (0.066 mole) of 9- fluorenyl bromide (prepared in accordance with the procedure of Witting and Felletschin, Ann.,

155, 138 (1944) in cc. of acetone was added 9.0 g. (0.06 mole) of 4-n-amyl pyridine. After refluxing for 17 hours the solution was concentrated under diminished pressure; the residual oily material crystallized. It was recrystallized once from isopropanol-ether. M. P. 204-204.5 C. Yield 20.0 g. (85%) Analysis for C23H24NBr:

Calculated: C, 70.0; H, 6.13 Found: C, 69.81; H, 6.12

EXAMPLE 3 1-benzohydryl-4-gamma-bhenylpropylpyrz'dz'nium bromide 8.3 g. (0.042 mole) of 4-gamma-phenylpropylpyridine was dissolved in 20 cc. of'acetone (reagent) and cooled. 10.4 g. (0.042 mole) of benzohydryl bromide dissolved in 10 ce. ofreagent acetone was added with swirling to the pyridine solution. (No immediate reaction was observed and the solution was allowed to stand overnight in the dark at room temperature.

The quaternary salt did not crystallize overnight but separated at once after cooling and scratching. It was recrystallized from absolute ethanol to a constant melting point of 175-177" C. (sintering at 136-138 C.) 4.7 g. (39.2%) of product was obtained.

Analysis for C27H26NBII V v Calculated: C, 73.0%; H, 5.90% Found: C, 72.71%; H, 5.99%

EXANDPLE 4 This was prepared in the same manner as Example .3 using acetone solutions of 9.4 g. (0.046 mole) of 4-(2-methyloctyl) pyridine and 11.4 g. (0.046 mole) of benzohydryl bromide. The quaternary did not separate overnight, but did immediately after cooling and scratching. Re- .crystallized to a constant melting point from reagent acetone. 2.7 g. (13.0%) of a product melting at 140-141 C. was obtained,

Analysis for C27H34NB1:

Calculated: C, 71.7; H, 7.58 Found: C,71.52; H, 7.70

EXAMPLE "5 1 -benzohydryZ-4- (5 mom l) pyridinium bromide Following the procedure of Example 3, 29.0 g. (0.15 mole) of 4-(5'nonyl)pyridine and 41.5 g. (0.165 mole) of benzohydryl bromidew'ere mixed in acetone solution. The product crystallized out the next day and was recrystallized twice from isopropanol and once from methyl isobutyl ketone. 49.3 g. (65%) of a product melting at 167-168 C. was obtained.

Analysis for C2-7H34NBIZ Calculated: C,71.6; H, 7.58 Found: C, 70189; H, 7.95

EXAMPLE. 6

1 -benzyl-4-n-amylpyridinium bromide 37.6 g. (0.22 mole) of benzyl bromide in 10 cc. of reagent acetone was added to a solution of 29.8 g. (0.2 mole) 'of4-n-a-my1 pyridine in 75cc. of reagent acetone. Within a few minutes the solution was very warm and when it was cooled, a white solid was precipitated. Recrystallized from acetone. 58.9 g. (91.8%) of material melting at 170-171.5 C, was obtained.

Analysis for Ci'zHzzNBl:

Calculated: C, 63.8; H, 6.90 Found: C, 63.89;, H, 7.21

"OH once, M. P. 169-172 C Analysis for C1sH15NBr2:

4 EXAMPLE 7 I-benaohydryl 4 (4 ethylcycloherylmethyl) pyridim'um bromide Using the same procedure as for Example 3, 8.4 g. (0.041 mole) of 4-(4'-ethylcyclohexylmethyl) pyridine and 10.1 g. (0.041 mole) of benzohydryl bromide were mixed. After stand- -ing overnight, the quaternary was crystallized by cooling and scratching, It was recrystallized twice from methyl ethyl ketone, 1.6 g. (8.6%) of material of melting point 150.5-152.5 C. was obtained.

Analysis for C27H33NB1.

Calculated: C, 71.40; H, 7.37 Found: C, 71.70; H, 7.24

EXAMPLE 8 I 1-ben.eohydryZ-4-n-herylp'yridinium bromide Following the procedure of Example .3, 12.7 g. -;(0.-077 mole) of 4-n-hexyl pyridine and 20.9 g. (0.085 mole) of benzohydryl bromide were mixed in acetone solution. The quaternary crystallized during the night. It was recrystallized from isopropanol, 20.0 g. (63%) of a product melting at 127.5- C. was obtained.

Analysis for C24H28NBI'I Calculated: C, 70.3; H, 6.82 Found: C, 70.47; H, 6.95

EXAMPLE 9 1-methyl-4mamylpyridinium iodide Analysis for CnI-ImNI:

Calculated: C, 45.4; H, 6.23 Found: C, 45.77; H, 6.27

EXAMPLE 10 1-.benzohydryle3-bromopyridinium bromide To a cooled acetone solution (100 ml.) of benzohydryl bromide (61 g.) (0.25 mole) was added 31.6 g. (0.2 mole) of B-bromopyridine. After standing at room't'emperature for 15 hours, the mixture was refluxed for one hour, cooled in ice and filtered. The filtrate and washings wererefiuxed for a further 44 hours, yielding an additional 28.1 g. of material. Total yield-68.4 g. (84.3%) M. P. -174 C. The compound was recrystallized from Et OH twice, from Me Calculated: C, 53.4; H, 3.74 Found: C, 53.45; H, 3.73

EXAIVHPLE 1 1 1 p nitrobenzyl-e -a '-ethylcyclohexylmethyl) pyridz'm'um bromide 4,8 g. (0.024 mole) of p-nitrobenzylbromide in 35 ml. of acetone was added to 4.1 g. (0.022 mole) of 4-(4'-ethylcyclohexylmethyl)pyridine in 15 00.01 acetone. The mixture wasr'efluxed for 30 minutes, cooled and placed in the-dark until the next day. The solvent was removed under diminished pressure and the residual gum was set up by repeated scratching and washing with ether. 8.2 g. (89%) M. P. 140-161 C. The material was recrystallized from MIBK to a melting point of. 177-180 C. 3.2 g. (35%).

Analysis for CziHzqozNzBrz Calculated: C, 60.1; H, 6.49 Found: C, 60.06; H, 6.31

EXAMPLE 3 12 1 -a-naphthylmethyl-4-n-amylpyridinium chloride 37.4 g. (0.25 mole) of 4-n-amylpyridine was addedwith cooling to a solution of 48.5 g. (0.27 mole) of a-chloromethylnaphthalene in 75 cc. of acetone. Standing for a week in darkness produced only a change in color of the solution.

. The solution was refluxed for four hours, cooled,

and a large volume of dry ether added. The brown gum which precipitated set up afterlong scratching and cooling. Crude yield--78.0 g. (87%) M. P. 135-l52 CLZ Recrystallized from n-propanol-ether and again from acetone to M. P. 159.5-160.5 C. I Yield 34.7 g. (38.8%).

Analysis for C21H24NCl:

Calculated: C. 77.5; H, 7.42 Found: C. 76.88; H, 7.46

" EXAMPLE 13 r ben ohydryz-s-carbethowy ridmwm bromide hemihydrate 30.2 g. (0.2 mole) of ethyl nicotinate, 54.4 g. (0.22 mole) of benzohydryl bromide and 100 cc. of acetone were mixed and refluxed for 15 hours. The vacetonewas removed under reduced pressure, leaving a red-brown gum which would not crystallize. The gum was washed several times with dry ether and the residual ether removed underdiminished pressure on the steam bath. The gum finally crystallized from acetone on standing overnight at 5 C. Recrystallized three times from acetone to M. P. 113-1l4 C. Yield 13.2, (16.6%).

Analysis for C21H2 O2NBr- /zI-I2O: Calculated: c, 61.9; H, 5.16 Found: C, 62.28; H, 5.26 0,6210; H, 5.32

-- EXAMPLE 14 1-benzohydryl-4-n amylpyridinium bromide masses. CzaI-IzeN'Br: ;;"Calculated: C, 69.8; H, 6.36 Found: C, 69.53; H, 6.54

EXAMPLE 15 l-benzohydrylpyridinium bromide 15.8 g (0.20 mole) of pyridine was dissolved in ml. of reagent acetone and cooled. 49.4 g. (0.20 mole) of benzohydryl bromide was dissolved in 25 ml. of reagent acetone and while'swirling was added to the pyridine solution. There was no immediate evidence of reaction, and the solution was placed in the dark and allowed to stand overnight at room temperature. v

The quaternary salt crystallized during the night. It was filtered off and'recrystallized from isopropanol to a constant meltingpoint. 32.7 g. (50.2%) of a product with a melting point 209- 213 C. was: obtained.

Analysis for ciaHis-BrN:

' Calculated: C, 66.3; H, 4.94 Found: C, 66.2; H, 5.03

EXAMPLE 16 1-beneohydryZ-4-ethylpyridinium bromide T This was prepared in the same manner as Example 15 using acetone solutions of 15.3 g. (0.143 mole) of 4-ethylpyridine and 35.3 g. (0.143.mole) of benzohydryl bromide. The quaternary did not crystallize overnight but did after scratching and stirring with a glass rod. It was dissolved in hot isopropanol, treated with charcoal, and filtered. The filtrate was cooled and on gradually adding ether, the quaternary crystallized. It was also recrystallized from isopropanol-ether. 15.4 g. (30.4%) of a product with a melting point'of 194196 C. was obtained.

Analysis for CzoHzoBrN:

Calculated: C, 67.8; H, 5.68 Found: C, 67.5; H, 5.76

EXAMPLE 17 1 -benzohydr yl-4-n-propylpyridinium bromide Using the same procedure as for Example 15, 18.1 g. (0.15 mole) of 4-n-propylpyridineand 37.0 g. (0.15 mole) of benzohydryl bromide were put together in acetone. The quaternary salt was crystallized the next morning by scratching with a glass rod. It was purified by two recrystallizations from isopropanol-ether solutions. 349g. (63.3%) ofmaterial with melting point 177-178 C. was obtained. Y

Analysis for C21H22B1'N:

Calculated: C, 68.6; H, 6.02 Found: C, 68.6; H, 6.34

. 1s 1-beneohydryl-4-n-butylpyridinium bromide Using the same procedure as for Example 15', 16.6 g. (0.123 mole) of 4-n-butylpyridine and 30.4 g. (0.123 mole) of benzohydryl bromide were put together in the acetone solution. The rest of the procedure is exactlyv like 664-25. 17.2 (36.6%) of material with a melting point 134- 135 C. was obtained.

Analysis for CzzHziBrNz Calculated: C, 69.2; H, 6.33

Found: C, 69.4; H, 6.63

EX MP E 19 s g 1 -benzohyd1'yl-Lbpzylpgridihium bromide A i In the same manner as in Example 15, 8.1 g. (0.048 mole) of 4-benzylpyridine and 11.8 g. (0.048. mole). of benzohydryl bromide were put together in acetone.

j The quaternary crystallized after cooling and scratching. Itwas recrystallizedtwi'ce from iso propanol after treating with charcoal in the isopropanol solution and filtering. 8.9 g. (44.7%) of productwith a melting point 169-170 C.Was obtamed. Analysis for CzsHzzBrN:

Calculated: (1,723.; H, 5.33

Found: C, 72.0; H, 538

- EXAMPLE 20 H .1wenzohydryl--n-octylpyridinium bromide With the same procedure as inExample .15, 8.0 g. (0.042 mole) of 4-n-octylpyridine and .103 g. (0.042 mole) of benzohydryl'bromide 'wereput together in acetone.

The product crystallized on cooling and scratching. It was recrystallized from acetoneether. 62 g. (33.9%) of material with a melting point of 150-151 C. was obtained.

Analysis for CzI-IaaBrN Calculated: C, 11.3; H. 7.34 Found: .C, 71.6; 11 7.3.4

EXAMPLE 21 1-benzohydryl-4 m nonylmlridmzum bromide 813 g. (0.040 mole) of 4-n-nonylpyridine and 10.0 g. (0.040mole) of benzohydryl bromide "were treated in exactly the same manner as in 730-46. 650 g. (32.0%) of material melting at 1'58-I59"'C. was obtained.

Analysis for C2'IH34BI'N Calculated: C, 71.8; .H, 758 Found: C, 71.8; H.754

EXAMPLE 22 I-bnzohydrgl 2 p hydroazyethyl pyridim'um bromide A mixture of.12.4 g. (0.1 mole) of 2-;9-hydroxyethylpyridine and 24.7 g. (0.1 mole) of hemehydryl bromide was allowed to stand at room temperature in a stoppered flask for two days.

The yellow-white crystalline mass which had formed was crystallized from 'isopropanol to obtain 143g. (38.8% yield) of white 'crystals,.M. JP. 150-l'5l C. Recrystallization from absolute alcohol raised the melting point to .151. C. The compound was dried in vacuo over phosphorus pentoxide before analysis.

Analysis for CzoHzoBrNO:

Calculated: C, 64.9,; H, 5.41 Found: C, 64.8; 1-15.38

EXAMPLEQS 1'-- benzohydryl 4 )3 hydromypropylpyrz'dinium bromide mon'ohydmte To 24.7 g. (0.1 mole) of benzohydryl bromide was added 1317' g. (0.1 mole) of 4-B-hydroxypyridine. and the mixture was allowed tosta'nd for ten days at 5-10 C. The resulting semi-solid was crystallized from isopropanol to obtain 13.4 g. of white crystals, M413. l08-l15' C. Successive recrystallizations from absolut'e'ial'coholether and isopropanolv yielded :8)? g. ofcolorless crystals, M. P. 1l9-122 C.

Analysis for C21H22B1NO- H2O:

Calculated: C, 62.8; .H, 6.00 Found: C, 62.9;.l-I, 6.06

EXAMPLE '24 1-benzohyd'ryZ-4-n-amylpyridinium bromide A mixture of 14.9 g. (0.1 mole) of 4-n-amylpyridine and 24.7 g. (0.1 mole) of benzohydryl 8 bromide was placed in a tightly stoppered flask and allowed to stand at 5--10 C. for two weeks. The resulting White crystalline solid was then stirred with ethyl acetate and collected by suction; weight 28.0 g. (71% yield). Recrystallization from acetone afiorded 17.9 g. of white crystals, M. P. l33135 C.

Analysis for CzaHzeBrNz I Calculated: C, 69.8; H, 6.36 Found: C, 69.2;v H, 6.78

On long standing the compound changed to its higher melting from .M. P. 153154 C.

We do not limit ourselves to the specificallymentioned times, temperatures, quantities, chemicals or steps of procedures, since these are given simply to clearly describe the invention and they may be varied without going beyond the scope of the invention.

I claim:

"1. A new class of compounds having the general formula R1 Ce wherein R represents ra member of the group consisting of alkylcontaining two to twenty carbon atoms, hydroxyalkyl containing two to twenty carbon atoms, carboalkoxy' and halogen, X represents a member of the group consisting of chloride, bromide and iodide, R1 and R2 represent .a member of the group containing. phenyLnapthyl, alkylphenyl, halogenated phenyl, alkoxyphenyl and nitrophenyl and R1 and R2 when :taken together with the adjacent -CH- group represent Q-fiuorenyl.

2. The compound 1 -benzohydryli-n-amylpyridinium bromide.

3. The compound l-benzohydryl-4-n-hexylpyridinium bromide.

4. The compound 1 benzohydryl 4 n-butylpyridinium bromide-. p

5. The compound 1-benzohydryl-4 ethy1pyridinium bromide.

6. The compound 1-benzehydryl-4 n propylpyridinium bromide.

LEE C. CHENEY.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,446,792 Shelton Aug. 10, I948 FOREIGN PATENTS Number Country Date 381,180 Germany of. 1921 OTHER -REFERENCES Krohnke, Berichte, 71B, pp. 2587 and 2591'and 2592 (1938).

J. Amer. Chem. -Soc., '68 (1946), 'pp. 2011-2013. 

1. A NEW CLASS OF COMPOUNDS HAVING THE GENERAL FORMULA 